The goal for Project 1 is to develop stocks of recombinant retroviral and adeno-associated viral vectors containing an HIV-regulated diphtheria toxin A chain gene. Based on our previous studies, such vectors should confer resistance to HIV infection, due to activation of the toxin gene early in HIV infection, before production of viral progeny. We will optimize conditions for efficient transduction into human peripheral blood mononuclear cells and bone marrow cells in culture, and rigorously assay for HIV production in transduced cells. I collaboration with Project 9001 we will also examine the in vivo anti- HIV properties of these vectors in the SCID/AIDS mouse model. Project 1 will additionally supply all HIV-regulated toxin constructs to Projects 2 for their studies. The experiments described here should lead directly to preclinical safety and toxicity studies for HIV-regulated toxin gene expression as a therapy for AIDS, where the immune system would be reconstituted with self-renewing, immune-competent cells which are resistant to HIV infection.